25 Nov 2025
What is the maternal hyperthermia critical stage(s)?
Li and Shiota (1999) emersed the posterior 2/3rds of pregnant mice for 15 minutes at 38 degrees C (controls) or for 15 minutes at 42 or 10 minutes at 43 degrees at various times after conception and determined the effect of the hyperthermic exposures on vertebral and rib patterns. Noon on the day after overnight mating was taken as Day 0.5 when a vaginal plug was observed.
All the offsprings of control mice had 26 pre-sacral vertebrae (PSV). 81% had the typical pattern of 7 cervical vertebrae, 13 thoracic vertebrae, and 6 lumbar vertebrae, with 7 of the ribs attached to the sternum and 4 sternebrae. The remaining 19% had either 13 vertebral ribs with 8 sternal ribs or 14 thoracic vertebrae and 5 lumbar vertebrae with either 7 or 8 attached to the sternum.
For the offspring of heat-treated mice they reported on the skeletal changes in animals with 24 or 25 PSV, indicating transformation of some pre-sacral vertebrae into a more cranial identity. The following vertebral and rib changes scored are listed from anterior to posterior: The first cervical vertebra fused to the occipital bone, an anterior tuberculi on the 5th cervical vertebra (normally on the 6th), only 6 cervical vertebrae, ribs on the 7th cervical vertebrae, only 6 sternal ribs (normally 7 or 8), 3 sternebrae (normally 4), 12 thoracic vertebrae, 5 lumber vertebrae. The table below shows the % of mice with 24 or 25 PSV for the various treatments. Also shown are the number of somites observed at these times by Tam (1981).
​ Treatment time (Days)
Treatment temperature 7.5 8.5 9.5
​
42 27% 47% 32%
​
43 49% 95% 53%
​
Somite number 6 23
Sensitivity shifted from anterior to posterior as treatment time increased. Clearly the 43 treatment is were more effective, even the exposure time was less. Almost all the mice receiving this treatment at 8.5 Days showed a transformation. The lower responses at 7.5 and 9.5 days could be for two reasons: the sensitivity of the region could be less or some slower progressing embryos may have been treated too early to affect the PSV region or the faster progressing were treated too late.
We are most interested in the period when the cervical region would be sensitive. All the effected mice treated at 7.5 Days showed changes in the cervical region while none of those treated at 8.5 Days did, so this sensitive time ended some time in this interval. The boundary between the cervical and thoracic occurs at the midpoint of the 12th somite. Tam (1981) placed the formation of the first somite at 8.3 days and the 12th somite at around Day 8.8. Note that the Tam saw a continuing slowing in the rate of somite formation so the rate of formation for the early somites is likely faster than the usually quoted rate of about 1 per every 2 hours. To get a more precise estimate of when hyperthermia results in changes at the C/T boundary, it is necessary to examine the timing of events from the gastrulation until the beginning of somitogenesis.
Deschamps et al. (1999) summarized their and others findings on the extent of Hox gene expression at various stages of mouse development. The earlies expression of 3' Hox genes occurs at the posterior end of the primitive streak in the presumptive extraembryonic mesoderm and then expands towards the node (anteriorly) successively in presumptive lateral plate, para-axial and axial mesoderm.
Their Figure 4 shows that by Day 7.5 Hoxb2 anterior expression in the paraxial mesoderm (precursor of the somites) is already anterior to the node, having migrated initially laterally from the streak. At the same time Hoxb8 expression is still confined to the posterior streak. It thus appears that when period when hyperthermia was observed to affect patterning in the neck region is somewhere around when the relevant Hox genes are first being expressed in the presumptive paraxial mesoderm,
In Exploration 1, the 3 studies of the time course of mouse maternal temperatures suggest that from 7 to 11 days post conception average daily temperature is relatively constant and higher than before or after and daily temperature variation is less (more homeothermic) than before.
It should be noted that Li and Shiota observed on Day 9.5 that hyperthermia could still affect the boundary between thoracic and lumbar vertebrae even though this was likely to be only a few hours before somites at this boundary would be expected to form. This would be long after the expression of the relevant Hox genes were first expressed. The shift in the boundary likely affects some aspect(s) of the segmentation clock.
It seems likely that the days long period of maximum temperature and homeothermy arose from the requirements for these conditions of many steps of development throughout this period. For example, even after the differentiation of cells in the neck region to the fate of becoming cardiac muscles cells, tight regulation of temperature would be required as they migrated to destinations in the thoracic region and were interacting with other cell populations.